Crystalline forms of the di-sodium salt of n-(5-chlorosalicyloyl)-8-aminocaprylic acid

ABSTRACT

The present invention relates to crystalline polymorphic forms of the di-sodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, pharmaceutical compositions containing the same, methods of preparing the same, and methods for facilitating the delivery of active agents with the same.

FIELD OF THE INVENTION

The present invention relates to crystalline forms of the di-sodium saltof N-(5-chlorosalicyloyl)-8-aminocaprylic acid (hereafter “5-CNAC”),pharmaceutical compositions containing the same, methods of preparingthe same, and methods for facilitating the delivery of active agentswith the same.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,773,647 discloses 193 delivery agent compounds,including N-(5-chlorosalicyloyl)-8-aminocaprylic acid (“5-CNAC”). Thesedelivery agent compounds increase the bioavailability of a broad rangeof biologically active agents, particularly biologically active agentsthat are not typically amenable to oral administration. U.S. PublishedApplication Nos. 2006/0078622 and 2006/0078623 discloses microparticlesor nanoparticles of delivery agent compounds, including 5-CNAC. U.S.Published Patent Application No. 2005/0054557 discloses pharmaceuticalcompositions that include parathyroid hormone, calcitonin and 5-CNAC.International Publication No. WO 00/59863 discloses the di-sodium saltof N-(5-chlorosalicyloyl)-8-aminocaprylic acid.

International Published Application No. WO 2005/01403 discloses use ofcalcitonin and 5-CNAC to treat osteoarthritis. U.S. PublishedApplication No. 2006/0106110 discloses a method of inhibiting plateletaggregation in a mammal comprising administering a modified amino acid,including 5-CNAC. International Published Application No. 03/015822discloses the use of 5-CNAC as an oral delivery agent for parathyroidhormone fragments. International Published Application No. WO 02/45754discloses pharmaceutical compositions comprising pharmacologicallyactive agents, crospovidone or povidone, and a delivery agent (e.g.5-CNAC).

SUMMARY OF THE INVENTION

The present invention relates to four crystalline forms of di-sodiumsalt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid (“5-CNAC”)(hereafter referred to as Forms I-IV), including an octahydrate of5-CNAC.

One embodiment of the invention is a pharmaceutical compositioncomprising (A) (i) one or more of Forms I-IV of 5-CNAC, and (B) anactive agent, such as calcitonin (e.g. salmon calcitonin) or humangrowth hormone (e.g. recombinant human growth hormone). According to apreferred embodiment, the pharmaceutical composition comprises at leastabout 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2,99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight of one of FormsI-IV of 5-CNAC, based upon 100% total weight of 5-CNAC in thepharmaceutical composition. According to another preferred embodiment,the pharmaceutical composition comprises at least about 20, 30, 40, 50,60, 70, 80, 90, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6,99.7, 99.8, or 99.9% by weight of one of Forms I-IV of 5-CNAC, basedupon 100% total weight of crystalline 5-CNAC in the pharmaceuticalcomposition.

Another embodiment is a pharmaceutical composition, such as a tablet,comprising at least one of Forms I-IV of 5-CNAC and at least one activeagent and/or pharmaceutically acceptable additive (such as thosedescribed below). A preferred active agent is calcitonin. Yet anotherpreferred active agent is a therapeutic mixture of calcitonin andparathyroid hormone (such as PTH[1-34]). Yet another preferred activeagent is insulin. Yet another preferred active agent is growth hormone(such as recombinant human growth hormone).

Yet another embodiment of the invention is a method for administering orfacilitating the delivery of an active agent in an animal (such as ahuman) by administering the pharmaceutical composition of the presentinvention.

Yet another embodiment is a method of treating Paget's disease orhypercalcemia, or treating or preventing osteoporosis in a mammal (suchas a human) in need thereof by orally administering an effective amountof the pharmaceutical composition of the present invention (e.g. apharmaceutical composition comprising Forms I, II, III, and/or IV of5-CNAC and (i) calcitonin (e.g. salmon calcitonin) or (ii) a combinationof calcitonin and parathyroid hormone or a fragment thereof (such asPTH[1-34]). Other diseases or conditions that may be treated, orphysiological affects achieved by orally administering an effectiveamount of the pharmaceutical composition of the present invention e.g. apharmaceutical composition comprising Forms I, II, III, and/or IV of5-CNAC and (i) calcitonin (e.g. salmon calcitonin) or (ii) a combinationof calcitonin and parathyroid hormone or a fragment thereof (such asPTH[1-34]) include diseases of the bone, bone pain (including painassociated with osteoporosis or cancer), osteoarthritis, abnormalresportion and turnover of sub-chondral bone, preserving and/orstimulating cartilage, inhibiting phosholipase A2 and/or collagenaseactivity, stimulating glycosaminoglycan and/or proteoglycan synthesis,stimulating new bone formation, acting on the inhomogeneity in densityor stiffness of the subchondral bone, acting on the inflammatoryprocess, leading to attenuations on pain in motion and related symptoms,reducing degenerative change in the joint in a patient.

Yet another embodiment is a method of preparing Form I of 5-CNACcomprising by (a) dissolving a monoethanol solvate of 5-CNAC in amixture of acetonitrile and water; and (b) cooling the solution preparedin step (a) at an effective temperature (e.g., to from about 5° C. toabout 15° C.) to yield Form I of 5-CNAC.

Yet another embodiment is a process for preparing Form I of 5-CNAC by(a) heating an aqueous solution of 5-CNAC (e.g., from about 40° C. toabout 70° C.); and (b) removing the water from the solution to yieldForm I of 5-CNAC (e.g., with a rotary evaporator and/or vacuum oven).

Yet another embodiment is a process for preparing a monoethanol solvateof 5-CNAC (such as Form II) by (a) adding sodium hydroxide to a solutionof N-(5-chlorosalicyloyl)-8-aminocaprylic acid and ethanol; and (b)precipitating Form II of 5-CNAC from the solution. Preferably, the molarratio of sodium hydroxide to N-(5-chlorosalicyloyl)-8-aminocaprylic acidis about 2:1.

Yet another embodiment is a process for preparing an octahydrate of5-CNAC (such as Form III) by maintaining (i) a monohydrate of 5-CNAC(such as Form I, IV, or a mixture thereof), (ii) a monoethanol solvateof 5-CNAC (such as Form II), or (iii) a mixture thereof at a relativehumidity of at least about 75% for a sufficient time to form theoctahydrate. According to one embodiment, the octahydrate is prepared atambient temperature or a temperature ranging from about 22° C. to about40° C. or about 50° C.

Yet another embodiment is a process for preparing Form IV of 5-CNAC by(a) dissolving 5-CNAC in methyl ethyl ketone at an elevated temperature(e.g., from about 30° C. to about 70° C.); and (b) cooling the methylethyl ketone solution of step (a) to yield Form IV of 5-CNAC.

Yet another embodiment is a process for preparing a mixture of Forms Iand IV of 5-CNAC by cooling a solution of 5-CNAC and acetone for asufficient time to produce the mixture of Forms I and IV. Optionally,the solution may also contain water.

The crystals prepared by any of the aforementioned procedures may berecovered by any method known in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 3, 4, and 5 are X-ray powder diffractograms (XRPDs) of FormsI-IV of 5-CNAC, respectively, as prepared in Examples 1-4 (The topspectra in FIG. 3 is the spectra for Form II).

FIGS. 2 and 6 are differential scanning calorimetry (DSC) analyses ofForms I and IV of 5-CNAC, respectively, as prepared in Examples 1 and 4.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “polymorph” refers to crystallographically distinct forms of asubstance.

The term “hydrate” as used herein includes, but is not limited to, acrystalline substance containing one or more molecules of water in adefinite ratio as an integral part of the crystal or a crystallinematerial containing free water.

The term “5-CNAC” as used herein refers to the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid. Unless otherwise noted, theterm “5-CNAC” as used herein refers to all polymorphs of 5-CNAC.

The term “5-CNAC monohydrate” as used herein refers to a crystallineform of 5-CNAC in which one molecule of water is associated with eachmolecule of 5-CNAC.

The term “5-CNAC octahydrate” as used herein refers to a crystallineform of 5-CNAC in which eight molecules of water are associated witheach molecule of 5-CNAC.

The term “solvate” as used herein includes, but is not limited to, amolecular or ionic complex of molecules or ions of a solvent withmolecules or ions of 5-CNAC. The term “co-solvate” as used hereinincludes, but is not limited to, a molecular or ionic complex ofmolecules or ions of two or more solvents with molecules or ions of5-CNAC.

The term “delivery agent” as used herein refers to 5-CNAC, including itscrystalline forms.

An “effective amount of drug” is an amount of the active agent (e.g.,heparin, calcitonin, parathyroid hormone, or recombinant human growthhormone) which is effective to treat or prevent a condition in a livingorganism to whom it is administered over some period of time, e.g.,provides a therapeutic effect during a desired dosing interval.Effective doses will vary, as recognized by those skilled in the art,depending on the route of administration, excipients present, andwhether the active agent is part of a co-therapy with other agents fortreating a condition.

The term “treat”, “treating”, or “treated” refers to administering anactive agent with the purpose to cure, heal, alleviate, relieve, alter,remedy, ameliorate, improve, or affect a condition (e.g., a disease),the symptoms of the condition, or the predisposition toward thecondition.

An “effective amount of delivery agent” is an amount of the deliveryagent which promotes the absorption of a desired amount of the activeagent via any route of administration (such as those discussed in thisapplication including, but not limited to, the oral (e.g., across abiological membrane in the gastrointestinal tract), nasal, pulmonary,dermal, vaginal, and/or ocular route).

The term “calcitonin” as used herein refers to all forms of calcitonin,including, but not limited to, human, salmon, pig and eel calcitonin,including natural, synthetic or recombinant sources thereof, as well ascalcitonin derivatives such as 1,7-Asu-eel calcitonin. A preferredcalcitonin is synthetic salmon calcitonin.

The term “parathyroid hormone” refers to all forms of parathyroidhormone, natural and synthetic, its fragments and agonists. For example,it may include, but is not limited to, human parathyroid hormone[1-36]and human parathyroid hormone[1-34].

The term “insulin” refers to all forms of insulin, natural and syntheticincluding, but not limited to, recombinant human insulin.

The term “growth hormone” refers to all forms of growth hormone, naturaland synthetic including, but not limited to, human growth hormone (e.g.,recombinant human growth hormone).

The term “fragments” of active agents, as used herein, refers totruncated forms of active agent that provides, upon administration to asubject, a similar physiological effect as the non-truncated activeagent. The term “analogs” of active agents, as used herein, refers toslightly modified forms of active agent that provides, uponadministration to a subject, a similar physiological effect as theactive agent from which the analog is based. It is understood thatanalogs of active agents (e.g. insulin analogs disclosed in U.S. Pat.No. 5,474,978) and fragments of active agents (e.g. the PTH fragmentsdisclosed herein) can be administered with forms I-IV of 5-CNAC withsimilar efficacy as administration of the active agent (e.g. insulin andPTH) itself with forms I-IV of 5-CNAC.

As used herein, the term “about” means within 10% of a given value,preferably within 5%, and more preferably within 1% of a given value.Alternatively, the term “about” means that a value can fall within ascientifically acceptable error range for that type of value, which willdepend on how qualitative a measurement can be given the availabletools.

5-CNAC Monohydrate Form 1

Form I of 5-CNAC is a monohydrate. Form I is the most stable of FormsI-IV at room temperature. According to differential scanning calorimetry(DSC), Form I has a first endothermic transition with an onsettemperature of about 69° C. (69.3° C.) and peaking at about 76° C.(75.2° C.) followed by a second broad endothermic event having an onsettemperature of about 98° C. and peaking at about 140° C. (141.2° C.)(see FIG. 2). Form I of 5-CNAC has an XRPD pattern substantiallyidentical to that shown in FIG. 1. For instance, Form I exhibits acharacteristic peak at 15.5° 2θ±0.2 or 0.1° 2θ. Characteristic XRPD peaklocations (expressed in degrees 2θ±0.2, 0.1, 0.05, or 0.01° 2θ) andd-spacing for Form I are provided in Table 1 below.

TABLE 1 Characteristic XRPD Peaks (expressed in degrees 2θ) of Form I of5-CNAC 2-theta d-Value (Å) Refraction angle (deg) Relative Intensity (%)11.788 7.5 100 8.507 10.4 4 6.238 14.2 4 5.907 15.0 6 5.717 15.5 175.506 16.1 5 4.822 18.4 59 4.271 20.8 13 3.770 23.6 5 3.693 24.1 6 3.63424.5 16 3.590 24.8 17 3.507 25.4 12 3.351 26.6 7 3.279 27.2 5 3.244 27.57 3.018 29.6 9 2.840 31.5 6

Form I may be prepared by the procedures described above and in Example1 below.

The present invention also provides a pharmaceutical compositioncontaining Form I of 5-CNAC in which less than 90, 80, 70, or 60% of the5-CNAC is crystalline (based on 100% total weight of 5-CNAC).

The present invention also provides a pharmaceutical composition, suchas a tablet, comprising a milled (e.g., ball milled) or directlycompressed mixture of Form I of 5-CNAC and at least one active agentand/or pharmaceutically acceptable additive (such as those describedbelow). Preferably, the pharmaceutical composition (or milled ordirectly compressed mixture) includes at least 50, 60, 70, 80, 90, 95,96, 97, 98, or 99% by weight of Form I based on the total weight of5-CNAC in the pharmaceutical composition (or milled or directlycompressed mixture).

5-CNAC Form II

Form II is a monoethanol solvate of 5-CNAC. Form II of 5-CNAC has anXRPD pattern substantially identical to that shown in FIG. 3. Forinstance, Form II exhibits a characteristic peak at 16.5° 2θ±0.2 or 0.1°2θ. Characteristic XRPD peak locations (expressed in degrees 2θ±0.2,0.1, 0.05, or 0.01°2θ) and d-spacing for Form II are provided in Table 2below.

TABLE 2 Characteristic XRPD Peaks (expressed in degrees 2θ) of Form IIof 5-CNAC 2-theta d-Value (Å) refraction angle 11.788 7.5 6.282 14.15.373 16.5 4.796 18.5 3.562 25 3.427 26

Form II of 5-CNAC may be prepared as described above and in Example 2.

5-CNAC Octahydrate Form III

Form III is an octahydrate of 5-CNAC. Form III is unstable at a relativehumidity below about 50%. Form III of 5-CNAC has an XRPD patternsubstantially identical to that shown in FIG. 4. For instance, From IIIexhibits a characteristic peak at 4.80°2θ±0.2 or 0.10 2θ. CharacteristicXRPD peak locations (expressed in degrees 2θ±0.2, 0.1, 0.05, or 0.01°2θ) and d-spacing for Form III are provided in Table 3 below.

TABLE 3 Characteristic XRPD Peaks (expressed in degrees 2θ) of Form IIIof 5-CNAC 2-theta d-Value (Å) Refraction angle (deg) Relative Intensity(%) 18.412 4.8 100 8.507 10.4 6 7.564 11.7 11 6.068 14.6 32

Form III may be prepared as described above and in Example 3. Forexample, Form III can be made by storing disodium 5-CNAC (such as itsethanol solvate) at 75% relative humidity (or higher) for at least sixdays.

The present invention also provides a pharmaceutical composition, suchas a tablet, comprising a directly compressed mixture of Form III of5-CNAC and at least one active agent and/or pharmaceutically acceptableadditive (such as those described below). Preferably, the pharmaceuticalcomposition (or directly compressed mixture) includes at least 50, 60,70, 80, 90, 95, 96, 97, 98, or 99% by weight of Form I based on thetotal weight of 5-CNAC in the pharmaceutical composition (or directlycompressed mixture).

5-CNAC Monohydrate Form IV

Form IV of 5-CNAC is a monohydrate. Form IV of 5-CNAC has an XRPDpattern substantially identical to that shown in FIG. 5. For instance,From IV exhibits a characteristic peak(s) at 7.2° and/or 18.2° 2θ±0.2 or0.1° 2θ. Characteristic XRPD peak locations (expressed in degrees2θ±0.2, 0.1, 0.05, or 0.01° 2θ) and d-spacing for Form IV are providedin Table 4 below.

TABLE 4 Characteristic XRPD Peaks (expressed in degrees 2θ) of Form IVof 5-CNAC 2-theta d-Value (Å) Refraction angle (deg) Relative Intensity(%) 12.279 7.2 52 4.875 13.2 100 3.605 24.7 7

Form IV may be prepared as described above and in Example 4.

The present invention also provides a pharmaceutical compositioncontaining Form IV of 5-CNAC in which at least 50, 60, 70, 80 or 90% ofthe 5-CNAC is crystalline based on 100% weight of 5-CNAC.

Mixture of 5-CNAC Forms I and IV

Forms I and IV of 5-CNAC are monohydrates. Characteristic XRPD peaklocations (expressed in degrees 2θ±0.2, 0.1, 0.05, or 0.01° 2θ) andd-spacing for the mixture are provided in Table 5 below.

TABLE 5 Characteristic XRPD Peaks (expressed in degrees 2θ) of Mixtureof Forms I and IV of 5-CNAC 2-theta d-Value (Å) Refraction angleRelative Intensity 12.452 7.1 9 11.788 7.5 100 8.507 10.4 4 6.238 14.2 35.907 15.0 5 5.717 15.5 16 5.506 16.1 4 4.822 18.4 60 4.251 20.9 113.770 23.6 4 3.693 24.1 5 3.634 24.5 10 3.576 24.9 11 3.507 25.4 113.351 26.6 5 3.279 27.2 4 3.244 27.5 6 3.008 29.7 6 2.840 31.5 5

The mixture can be prepared as described above and in Example 5.

The crystals prepared by any of the aforementioned procedures may berecovered by any method known in the art.

Active Agents

Active agents suitable for use in the present invention includebiologically active agents and chemically active agents, including, butnot limited to, pesticides, pharmacological agents, and therapeuticagents. Suitable active agents include those that are rendered lesseffective, ineffective or are destroyed in the gastro-intestinal tractby acid hydrolysis, enzymes and the like. Also included as suitableactive agents are those macromolecular agents whose physiochemicalcharacteristics, such as, size, structure or charge, prohibit or impedeabsorption when dosed orally.

For example, biologically or chemically active agents suitable for usein the present invention include, but are not limited to, proteins;polypeptides; peptides; hormones; polysaccharides, and particularlymixtures of muco-polysaccharides; carbohydrates; lipids; small polarorganic molecules (i.e., polar organic molecules having a molecularweight of 500 daltons or less); other organic compounds; andparticularly compounds which by themselves do not pass (or which passonly a fraction of the administered dose) through the gastro-intestinalmucosa and/or are susceptible to chemical cleavage by acids and enzymesin the gastro-intestinal tract; or any combination thereof.

Further examples include, but are not limited to, the following,including synthetic, natural or recombinant sources thereof: growthhormones, including human growth hormones (hGH), recombinant humangrowth hormones (rhGH), bovine growth hormones, and porcine growthhormones; growth hormone releasing hormones; growth hormone releasingfactor, interferons, including α (e.g., interferon alfacon-1 (availableas Infergen® from InterMune, Inc. of Brisbane, Calif.)), β and γ,interleukin-1; interleukin-2; insulin, including porcine, bovine, human,and human recombinant, optionally having counter ions including zinc,sodium, calcium and ammonium; insulin-like growth factor, includingIGF-1; heparin, including unfractionated heparin, heparinoids,dermatans, chondroitins, low molecular weight heparin, very lowmolecular weight heparin and ultra low molecular weight heparin;calcitonin, including salmon, eel, porcine and human; erythropoietin;atrial naturetic factor; antigens; monoclonal antibodies; somatostatin;protease inhibitors; adrenocorticotropin, gonadotropin releasinghormone; oxytocin; leutinizing-hormone-releasing-hormone; folliclestimulating hormone; glucocerebrosidase; thrombopoietin; filgrastim;prostaglandins; cyclosporin; vasopressin; cromolyn sodium (sodium ordisodium chromoglycate); vancomycin; desferrioxamine (DFO);bisphosphonates, including alendronate, tiludronate, etidronate,clodronate, pamidronate, olpadronate, and incadronate; parathyroidhormone (PTH), including its fragments; anti-migraine agents such asBIBN-4096BS and other calcitonin gene-related proteins antagonists;glucagon-like peptide 1 (GLP-1); Argatroban; antimicrobials, includingantibiotics, anti-bacterials and anti-fungal agents; vitamins; analogs,fragments, mimetics or polyethylene glycol (PEG)-modified derivatives ofthese compounds; or any combination thereof. Non-limiting examples ofantibiotics include gram-positive acting, bacteriocidal, lipopeptidaland cyclic peptidal antibiotics, such as daptomycin and analogs thereof.

According to one embodiment, the active agent is a pharmacologicallyactive peptide, such as a bone active agent (e.g. calcitonin). Boneactive agents include classes of agents which display in vivopharmacological activity in animals such as stabilization, healing, orgrowth of bone, deceleration or inhibition of bone turnover,deceleration or inhibition of bone resorption, inhibition of osteoclastactivity, and stimulation of osteoblast activity. Some of these agentsmay be peptidic, for example, calcitonins, parathyroid hormone (PTH),PTH fragments (e.g., PTH[1-34]), Transforming Growth Factors (TGFs), andanalogs and fragments of any of the above. The bone active agents mayalso be small molecule non-peptidic structures which show in vivopharmacological bone activities as described above in this paragraph.

A known class of such pharmacologically active agents, calcitonins, havevarying pharmaceutical utility and are commonly employed in thetreatment of, e.g., Paget's disease, hypercalcemia and osteoporosis(including, but not limited to, postmenopausal osteoporosis). Variouscalcitonins, including salmon, pig and eel calcitonin are commerciallyavailable and commonly employed for the treatment of, e.g., Paget'sdisease, hypercalcemia of malignancy and osteoporosis. The calcitonincan be any calcitonin (e.g., human, salmon, pig or eel), includingnatural, synthetic or recombinant sources thereof, as well as calcitoninderivatives such as 1,7-Asu-eel calcitonin. The compositions cancomprise a single calcitonin or any combination of two or morecalcitonins. The preferred calcitonin is synthetic salmon calcitonin.

The calcitonins are commercially available or may be synthesized byknown methods.

When the pharmacologically active agent is salmon calcitonin, theappropriate dosage will, of course, vary depending upon, for example,the host and the nature and severity of the condition being treated.Suitable dosage amounts are provided in International Publication Nos.WO 2004/012772, WO 2005/004900, and WO 2005/014031, all of which arehereby incorporated by reference. An oral human dose of salmoncalcitonin is typically in the range of about 0.05 mg −5 mg, preferablyabout 0.1 mg-2.5 mg, when administered in combination with an oraldelivery agent (e.g. 5-CNAC). According to one embodiment, from about0.4 mg to about 2.5 mg of salmon calcitonin is administered daily to apatient, e.g., a human such as an average human of about 70 kg. Morepreferably, from about 0.8 to about 1.2 mg, e.g., about 1 mg, isadministered daily. Also preferred are doses less than 1 mg but higherthan 0.4 mg.

Suitable dosage amounts of parathyroid hormone are provided inInternational Publication Nos. WO 2005/002549, WO 03/015822, and WO02/098453, all of which are hereby incorporated by reference. The amountof parathyroid to be administered is an amount effective to achieve thephysiological conditions desired. In one embodiment the amount ofparathyroid component (e.g., PTH, PTH[1-28]-PTH[1-41]) is such that itprovides a daily administered dose of PTH component of from about 0.001μg/kg to about 10 mg/kg of animal body weight, or from about 1 μg/kg toabout 6 μg/kg of animal body weight. Unit dosage forms may contain, forexample, 800 μg of PTH component. Particular PTH amounts for specificapplications will vary according to the age, size, sex and condition ofthe subject to be treated and can be determined by persons of ordinaryskill in the art.

Amounts of HGH or HGH component can also be determined by persons ofordinary skill in the art. In one embodiment, the amount of HGH (e.g.the 191 amino acid native species (somatropin)) or HGH component (e.g.the 192 amino acid N-terminal methionine (met) species (somatrem)) issuch that it provides in a unit dosage form of from about 10 mg to about300 mg of HGH or HGH component (e.g. 100 mg of HGH or HGH component).Particular HGH amounts for specific applications will vary according tothe age, size, sex and condition of the subject to be treated and can bedetermined by persons of ordinary skill in the art.

The pharmacologically active agent generally comprises from about 0.05percent to about 70 percent by weight relative to the total weight ofthe overall pharmaceutical composition, preferably an amount of fromabout 0.01 percent to about 50 percent by weight, more preferably about0.3 percent to about 30 percent by weight relative to the total weightof the overall pharmaceutical composition.

Pharmaceutical Compositions

The pharmaceutical composition is preferably in solid form and may be inthe form of a dosage form (e.g. a solid dosage form, such as a solidoral dosage form). The solid dosage form can be a capsule, tablet orparticle, such as a powder or sachet. The powder may be in the form of asachet that is mixed with a liquid and administered. Also the powder canalso be packed into capsules or pressed into tablets, or the powder maybe administered to the subject as-is.

Alternatively, the solid dosage form can be a topical delivery system,such as an ointment, cream or semi-solid. For example, the powders maybe added to topical excipients (e.g. polyethylene glycol) andadministered as an ointment.

The pharmaceutical composition can include a sustained release orcontrolled release system. Preferably, the solid dosage form is for oraladministration.

The amount of delivery agent in the solid dosage form is a deliveryeffective amount and can be determined for any particular compound orbiologically or chemically active agent by methods known to thoseskilled in the art.

Following administration, the active agent in the dosage unit form istaken up into circulation. The bioavailability of the active agent isreadily assessed by measuring a known pharmacological activity in blood,e.g., an increase in blood clotting time caused by heparin, or adecrease in circulating calcium levels caused by calcitonin.Alternately, the circulating levels of the active agent itself can bemeasured directly.

The solid dosage form may include pharmaceutically acceptable additives,such as excipients, carriers, diluents, stabilizers, plasticizers,binders, glidants, disintegrants, bulking agents, lubricants,plasticizers, colorants, film formers, flavoring agents, preservatives,dosing vehicles, surfactants, and any combination of any of theforegoing. Preferably, these additives are pharmaceutically acceptableadditives, such as those described in Remington's, The Science andPractice of Pharmacy, (Gennaro, A. R., ed., 19th edition, 1995, MackPub. Co.) which is herein incorporated by reference.

Suitable binders include, but are not limited to, starch, gelatine,sugars (such as sucrose, molasses and lactose), dibasic calciumphosphate dihydrate, natural and synthetic gums (such as acacia, sodiumalginate, carboxymethyl cellulose, methyl cellulose,polyvinylpyrrolidone, polyethylene glycol, ethylcellulose, and waxes.

Suitable glidants include, but are not limited to, talc, and silicondioxide (silica) (e.g, fumed silica and colloidal silicon dioxide).

Suitable disintegrants include, but are not limited to, starches, sodiumstarch glycolate, croscarmellose sodium, crospovidone, clays, celluloses(such as purified cellullose, methylcellulose, sodium carboxymethylcellulose), alginates, pregelatinized corn starches, and gums (such asagar, guar, locust bean, karaya, pectin and tragacanth gums). Apreferred disintegrant is sodium starch glycolate.

Suitable bulking agents include, but are not limited to, starches (suchas rice starch), microcrystalline cellulose, lactose (e.g., lactosemonohydrate), sucrose, dextrose, mannitol, calcium sulfate, dicalciumsulfate, and tricalcium sulfate.

Suitable lubricants include, but are not limited to, stearic acid,stearates (such as calcium stearate and magnesium stearate), talc, boricacid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride,polyethylene glycol, hydrogenated cottonseed, and castor oils.

Suitable surfactants include, but are not limited to, sodium laurylsulfate, hydroxylated soy lecithin, polysorbates, and block copolymersof propylene oxide and ethylene oxide.

The pharmaceutically acceptable inactive excipients may include polymersand inactive compounds which for example, aid the formulation ormanufacturing of the solid oral dosage form contemplated by the presentinvention or which may aid the release of the solid oral composition inthe gastro-intestinal environment.

In an additional embodiment of the present invention thepharmaceutically acceptable inactive excipient may be either or both ofthe polymers crospovidone or povidone.

The pharmaceutical inactive ingredients, referred to above, for exampleoptionally include crospovidones and povidones, which may be anycrospovidone and povidone. Crospovidone is a syntheticcrosslinkedhomopolymer of N-vinyl-2-pyrrolidone, also called1-ethenyl-2-pyrrolidinone, having a molecular weight of 1,000,000 ormore. Commercially available crospovidones include Polyplasdone XL,PolyplasdoneXL-10, Polyplasdone INF-10 available from ISP, Kollidon CL,available from BASF Corporation. The preferred crospovidone isPolyplasdone XL.

Povidone is a synthetic polymer consisting of linear1-vinyl-2-pyrrolidinone groups having a molecular weight generallybetween 2,500 and 3,000,000. Commercially available povidones includeKollidon K-30, Kollidon K-90F available from BASF Corporation andPlasdone K-30 and Plasdone K-29/32, available from ISP.

As mentioned above, the crospovidones and povidones are commerciallyavailable. Alternatively, they may be synthesized by known processes.

The crospovidone, povidone or combination thereof is generally presentin the compositions in an amount of from about 0.5 percent to 50 percentby weight relative to the total weight of the overall pharmaceuticalcomposition, preferably an amount of from 2 percent to 25 percent, morepreferably 5 percent to 20 percent by weight relative to the totalweight of the pharmaceutical composition.

Delivery Systems

The amount of active agent used in a pharmaceutical composition of thepresent invention is an amount effective to accomplish the purpose ofthe particular active agent for the target indication. The amount ofactive agent in the compositions typically is a pharmacologically,biologically, therapeutically, or chemically effective amount. However,the amount can be less than that amount when the composition is used ina dosage unit form because the dosage unit form may contain a pluralityof delivery agent compound/active agent compositions or may contain adivided pharmacologically, biologically, therapeutically, or chemicallyeffective amount. The total effective amount can then be administered incumulative units containing, in total, an effective amount of the activeagent.

The total amount of active agent to be used can be determined by methodsknown to those skilled in the art. However, because the compositions ofthe invention may deliver active agents more efficiently than othercompositions or compositions containing the active agent alone, loweramounts of biologically or chemically active agents than those used inprior dosage unit forms or delivery systems can be administered to thesubject, while still achieving the same blood levels and/or therapeuticeffects.

Generally, the weight ratio of delivery agent (e.g. 5-CNAC) to activeagent (e.g. HGH or HGH component, PTH or PTH fragment) ranges from about0.1:1 to about 300:1 or 1000:1. In one embodiment the weight ratio ofdelivery agent (e.g. 5-CNAC) to active agent (e.g. HGH or HGH component,PTH or PTH fragment) ranges from about 50:1 or 40:1 to about 0.5: or0.2:1. In one embodiment the weight ratio of delivery agent (e.g.5-CNAC) to active agent (e.g. HGH or HGH component, PTH or PTH fragment)ranges from about 10:1 to about 0.5:1 (e.g. 2:1). The weight ratio ofdelivery agent (e.g. 5-CNAC) is calculated based on the free acid formof the delivery agent. The weight ratio will vary according to theactive agent and the particular indication for which the active agent isadministered.

The presently disclosed delivery agents facilitate the delivery ofbiologically and chemically active agents, particularly in oral,sublingual, buccal, intraduodenal, intracolonic, rectal, vaginal,mucosal, pulmonary, intranasal, and ocular systems.

The compounds and compositions of the subject invention are useful foradministering biologically or chemically active agents to any animals,including but not limited to birds such as chickens; mammals, such asrodents, cows, pigs, dogs, cats, primates, and particularly humans; andinsects.

The compounds and compositions are particularly advantageous fordelivering chemically or biologically active agents that would otherwisebe destroyed or rendered less effective by conditions encountered beforethe active agent reaches its target zone (i.e. the area in which theactive agent of the delivery composition is to be released) and withinthe body of the animal to which they are administered. Particularly, thecompounds and compositions of the present invention are useful in orallyadministering active agents, especially those that are not ordinarilyorally deliverable, or those for which improved delivery is desired.

The compositions comprising the compounds and active agents have utilityin the delivery of active agents to selected biological systems and inan increased or improved bioavailability of the active agent compared toadministration of the active agent without the delivery agent. Deliverycan be improved by delivering more active agent over a period of time,or in delivering active agent in a particular time period (such as toeffect quicker or delayed delivery) or over a period of time (such assustained delivery).

Another embodiment of the present invention is a method for thetreatment or prevention of a disease or for achieving a desiredphysiological effect, such as those listed in the table below, in ananimal by administering the composition of the present invention.Specific indications for active agents can be found in the Physicians'Desk Reference (59^(th) Ed., 2005, Medical Economics Company, Inc.,Montvale, N.J.), which is herein incorporated by reference. The activeagents in the table below include their analogs, fragments, mimetics,and polyethylene glycol-modified derivatives.

Active Agent Disease and Physiological Effect Growth hormones (includinghuman Growth disorders; preventing muscle wasting recombinant growthhormone and growth- hormone releasing factors and its analogs)Interferons, including α, β and γ Viral infection, including chroniccancer, hepatitis, and multiple sclerosis Interleukins (e.g.Interleukin-1; interleukin-2) Viral infection; cancer; cell mediatedimmunity; and transplant rejection; Insulin; Insulin-like growth factorIGF-1 Diabetes Immune Globulins, such as IVIg smallpox, rabies, anddiphtheria, Alzheimer's Disease; Primary immunodeficiencies; AcuteGuillain-Barré syndrome; Chronic idiopathic demyelinating polyneuropathy(CIDP); Myasthenia gravis, polymyositis, and dermatomyositis; neonatalimmune thrombocytopenia, heparin-induced thrombocytopenia, andantiphospholipid antibody syndrome: Posttransfusion purpura. HeparinTreatment and Prevention of Thrombosis, including (Deep VeinThrombosis); prevention of blood coagulation Calcitonin Osteoporosis;diseases of the bone; bone pain: analgesic (including pain associatedwith osteoporosis or cancer) Erythropoietin, Pegylated erythropoietin.Anemia; HIV/HIV-therapy Associated Anemia; Chemotherapeutically-InducedAnemia Atrial naturetic factor Vasodilation Antigens Infection CPHPCReduction of amyloid deposits and systemic amyloidoisis often (but notalways) in connection with Alzheimer's disease, Type II diabetes, andother amyloid-based diseases Monoclonal antibodies To prevent graftrejection; cancer; used in assays to detect diseasesSomatostatin/octreotide Bleeding ulcer; erosive gastritis; varicealbleeding; diarrhea; acromegaly; TSH-secreting pituitary adenomas;secretory pancreatic tumors; carcinoid syndrome; reduce proptosis/thyroid-associated ophthalmopathy; reduce macular edema/retinopathy;decreases growth hormone and insulin-like growth factor Proteaseinhibitors HIV Infection/AIDS Adrenocorticotropin High cholesterol (tolower cholesterol) Gonadotropin releasing hormone Ovulatory disfunction(to stimulate ovulation) Oxytocin Labor disfunction (to stimulatecontractions) Leutinizing-hormone-releasing-hormone; Regulatereproductive function Leutinizing Hormone; follicle stimulating hormoneGlucocerebrosidase Gaucher disease (to metabolize lipoprotein)Thrombopoietin Thrombocytopenia Filgrastim (Granulocyte ColonyStimulating shorten the duration of chemotherapy-induced Factor);GM-CSF, (sargramostim) and their neutropenia and thus treat or preventinfection Pegylated forms in chemotherapy patients; Inhibit the growthof or to kill Mycobacterium Intracellular Avium Infection (MAC) RNAiHuntington, Alzheimers, Viral Infections (HIV, Hepatitis A, B or C,RSV), Cancers; Macular Degeneration Prostaglandins HypertensionCyclosporin Transplant rejection; psoriasis, inflammatory alopecias;Sjogren's syndrome; Keratoconjuactivitis Sicca Vasopressin NocturnalEnuresis; antidiuretic Cromolyn sodium; Asthma; allergies VancomycinTreat or prevent antimicrobial-induced infections including, but notlimitted to methacillin-resistant Staphalococcus aureus and Staph.epidermiditis gallium salts (such as gallium nitrate) Osteoporosis;Paget's disease; Inhibits osteoclasts; Promotes osteoblastic activity,hypercalcemia, including cancer related hypercalcemia, urethral (urinarytract) malignancies; anti-tumors, cancers, including urethral andbladder cancers; lymphoma; malignancies (including bladder cancer);leukemia; management of bone metastases (and associated pain); muliplemyeloma, attenuate immune response, including allogenic transplantrejections; disrupt iron metabolism; promote cell migration; woundrepair; to attenuate or treat infectious processes of mycobacteriumspecies, including but not limited to mycobacterium tubercolosis, andmycobacterium avium complex Desferrioxamine (DFO) Iron overloadParathyroid hormone (PTH), including its Osteoporosis; fragments.Diseases of the bone Antimicrobials Infection including but not limitedto gram- positive bacterial infection Vitamins Treat and prevent Vitamindeficiencies Bisphosphonates Osteoporosis; Paget's disease; bone tumorsand metastases (and associated pain); Breast cancer; including asadjuvant therapy for early stage breast cancer; management of bonemetastases (and associated pain), including bone metastases associatewith breast cancer, prostate cancer, and lung cancer; Inhibitsosteoclasts; Promotes osteoblastic activity; treat and/or prevent bonemineral density (bmd) loss; multiple myeloma; prevention of bonecomplications related to malignant osteolysis; fibrous dysplasia;pediatric osteogenesis imperfecta; hypercalcemia, urethral (urinarytract) malignancies; reflex, sympathetic dystropy synodrome, acute backpain after vertebral crush fracture, chronic inflammatory joint disease,renal bone disease, extrosseous calcifications, analgesic, vitamin Dintoxication, periarticular ossifications BIBN4096BS -(1-Piperidinecarboxamide. N- Anti-migraine; calcitonin gene- relatedpeptide [2-[[5-amino-1-[[4-(4-pyridinyl)-1- antagonistpiperazinyl)carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2- oxoethyl]-4(1,4-dihydro-2-oxo-3(2H0-quinazolinyl)-.[R-(R*,S*)]-) Glucagon improving glycemic control (e.g.treating hypoglycemia and controlling hypoglycemic reactions), obesity;a diagnostic aid in the radiogical examination of the stomach, duodenum,small bowel and colon; Treat acute poisoning With Cardiovascular Agentsincluding, but not limited to, calcium channel blockers, beta blockersGLP-1, Exendin - 3, Exendin - 4, Obestatin Diabetes; improving glycemiccontrol (e.g. treating hypoglycemia and controlling hypoglycemicreactions), obesity dipeptidyl peptidase IV (DPP-4) inhibitors Diabetes;improving glycemic control (e.g. treating hypoglycemia), obesityacyelovir, valacyclovir Used to treat herpes infections of the skin, lipand genitals; herpes zoster (shingles); and chickenpox HIV EntryInhibitors (e.g. Fuzeon) Inhibit entry of HIV into host cellsSumatriptin, almotriptan, naratriptan, anti-migraine serotonin agonistsrizatriptan, frovatriptan and eletriptan (piperidinyloxy)phenyl,(piperidinyloxy)pyridinyl, (piperidinylsulfanyl)phenyl and(piperidinylsulfanyl)pyridinyl compounds Neuraminidase inhibitors:peramivir, Antivirals zanamivir, oseltamivir, BCX-1898, BCX-1827,BCX-1989, BCX 1923, BCX 1827 and A315675; M2 inhibitors: amantadine,rimantadine; Nucleoside/Nucleotide Reverse Transcriptase Inhibitors,Non-nucleoside Reverse Transcriptase Inhibitors, Protease Inhibitors,Fusion inhibitors: thiovir, thiophosphonoformate, foscarnet,enfuviritide, zidovudine, didanosine, zalcitabine, stavudine,lamivudine, emtricitabine, abacavir, azidothymidine, tenofovirdisoproxil, delavridine, efavirenz, nevirapine, ritonavir, nelfinavirmesylate, saquinvir mesylate, indinavir sulfate, amprenavir, lopinavir,lopinavir, fosamprenavir calcium, atazanavir sulfate Peptide YY (PYY)and PYY-like Peptides (e.g. Obesity, Diabetes, Eating Disorders,Insulin- PYY[3-36]) Resistance Syndromes Apo a-1 and its mimetics (e.g.APP018) Decreases HDL; treats or prevents atherosclerosis, treatshypercholesterolemias Imitinab Used to treat chronic myeloid leukemia,and gastrointestinal stromal tumors influenza virus vaccine, types A andB (surface Prevents influenza infections antigen) ranibizumab To treator prevent macular degeneration (e.g., wet macular degeneration andage-related macular degeneration)

Another embodiment is a method of treating a disorder responsive to theaction of calcitonin, such as Paget's disease, hypercalcemia orosteoporosis (e.g. treating postmenopausal osteoporosis in women greaterthan five years postmenopause with low bone mass relative to healthypremenopausal women), in a mammal (e.g., a human) in need thereof byorally administering a pharmaceutical composition of the presentinvention which contains Forms I, II, III and/or IV of 5-CNAC andcalcitonin. Preferably, the pharmaceutical composition is administeredin the absence of food, advantageously a short interval prior to theconsumption of food, for instance, a short interval before a meal, so asto enhance the oral bioavailability of calcitonin.

Another embodiment is a method of treating a disorder responsive to theaction of human growth hormone, such as growth disorders (e.g. shortstature), in a mammal (e.g., a human) in need thereof by orallyadministering a pharmaceutical composition of the present inventionwhich contains Forms I, II, III and/or IV of 5-CNAC and human growthhormone. Other examples of conditions that can be treated, or effectsachieved with pharmaceutical compositions of the present invention thatinclude Forms I, II, III and/or IV of 5-CNAC and human growth hormoneinclude long-term treatment of pediatric patients who have growthfailure due to an inadequate secretion of endogenous growth hormone,long-term treatment of pediatric patients who have growth failure due toPrader-Willi syndrome (PWS), short stature associated with Turnersyndrome in patients whose epiphyses are not closed, idopathic shortstature, long term replacement therapy in adults with growth hormonedeficiency (GHD) of either childhood or adult-onset etiology (e.g.growth hormone deficiencies as a result of pituitary disease,hypothalamic disease, surgery, radiation therapy, chronic renalinsufficiency or trauma), and long-term treatment of growth failure inchildren born small for gestational age who fail to manifest catch-upgrowth by age 2.

Another embodiment is a method of treating a disorder responsive to theaction of parathyroid hormone, such as osteoporosis (e.g. postmenopausalwomen with osteoporosis who are at high risk for fracture), in a mammal(e.g., a human) in need thereof by orally administering a pharmaceuticalcomposition of the present invention which contains Forms I, II, IIIand/or IV of 5-CNAC and parathyroid hormone. Other examples ofconditions that can be treated, or effects achieved with pharmaceuticalcompositions of the present invention that include Forms I, II, IIIand/or IV of 5-CNAC and parathyroid hormone include increase in bonemass in men with primary or hypogonadal osteoporosis who are at highrisk for fracture.

Another embodiment is a method of treating a disorder responsive to theaction of Imitinab, such as chronic myeloid leukemia, andgastrointestinal stromal tumors, in a mammal (e.g., a human) in needthereof by orally administering a pharmaceutical composition of thepresent invention which contains Forms I, II, III and/or IV of 5-CNACand Imitinab.

Another embodiment is a method of treating a disorder responsive to theaction of influenza virus vaccine, such as influenza infections, in amammal (e.g., a human) in need thereof by orally administering apharmaceutical composition of the present invention which contains FormsI, II, III and/or IV of 5-CNAC and influenza virus vaccine.

Another embodiment is a method of treating a disorder responsive to theaction of ranibizumab, such as macular degeneration (e.g., wet maculardegeneration and age-related macular degeneration), in a mammal (e.g., ahuman) in need thereof by orally administering a pharmaceuticalcomposition of the present invention which contains Forms I, II, IIIand/or IV of 5-CNAC and ranibizumab.

The following examples illustrate the present invention withoutlimitation. All percentages are by weight unless otherwise specified.

DSC

The melting points cited were determined by differential scanningcalorimety (DSC). The quoted values were obtained with a Perkin ElmerDifferential Scanning Calorimeter DSC-7. The DSC curves were recordedusing a heating rate of 20 K/min and a sample mass of 1-3 mg.

XRPD

The Powder X-Ray diffraction analysis was done using a Scintag X1diffractometer and copper Kα₁ radiation.

Example 1 Preparation of Form I of 5-CNAC

Form I of 5-CNAC was prepared as follows. A 200 gallon glass-linedreactor was set up for atmospheric distillation. Cooling was applied tothe condenser and receiver. The reactor was purged with nitrogen. Thereactor was charged with 565 L of acetonitrile. The agitator was set at100 rpm. The reactor was charged with 13.7 kg of purified water and43.25 kg of 5-CNAC monoethanol solvate. The reactor contents were heatedto reflux causing distillate to begin collecting in the receiver.Atmospheric distillation was continued until approximately 102 L ofdistillate was collected. Heating of the reactor jacket was stopped anda mixture of 102 L of fresh acetonitrile and 2.5 kg of purified waterwere charged to the reactor. The reactor contents were cooled to between5 and 15° C. and agitate for between one and two hours. The resultantslurry was isolated by centrifugation. The wet cake was not washed. Thewet cake was dried in a vacuum oven at full vacuum between 75 and 85° C.for 48 hours. The yield of disodium 5-CNAC monohydrate was approximately40 kg for a yield of about 99.9%.

XRPD and DSC spectra for Form I as prepared above are shown in FIGS. 1and 2, respectively.

Example 1A Preparation of Form I of 5-CNAC

Form I was also prepared as follows. A 22 L, Pyrex glass, five-neck,round bottom flask was equipped with an overhead stirrer, thermocoupletemperature read out, and heating mantle. The flask was charged with2602.3 g of 5-CNAC and 4000 mL water. To this stirred slurry was added asolution of 660 g of sodium hydroxide dissolved in 2000 mL water. Themixture was heated to 55° C. and most of the solids dissolved. Theslightly hazy solution was hot filtered through Whatman #1 filter paperto remove the insoluble particulates. The filtrate was transferred tothe pot flask of a large laboratory rotary evaporator. The rotaryevaporator was operated with a bath temperature of 60° C. and a pressureof 60 mmHg. Water was removed from the disodium salt solution until asolid mass was obtained in the rotary evaporator pot flask. The vacuumwas released and pot flask removed from the rotary evaporator. Thesolids were scraped from the pot flask into trays. These trays were thenplaced in a vacuum oven and the solids dried at 60° C. and full vacuumfor 48 hours. The dried solids were run through a laboratory mill untilall the solids passed through a 35 mesh screen. The milled and sieveddisodium 5-CNAC monohydrate was put into trays and placed back into thedrying oven. Drying was continued at 45° C. and full vacuum giving2957.1 g of the desired product as a dry powder.

Example 2 Preparation of Form II of 5-CNAC

Form II of 5-CNAC was prepared as follows. Into a 200 gallon stainlesssteel reactor was charged 132 L of ethanol and 11.6 kg of sodiumhydroxide pellets. The reactor was heated to about 55° C. and held atthis temperature until the sodium hydroxide dissolved. The sodiumhydroxide/ethanol solution was cooled and maintained at a temperature ofat least 25° C. The sodium hydroxide/ethanol solution was sampled forbase assay by titration. Into a second 200 gallon glass-lined reactorwas charged 135 L of ethanol and 44.69 kg of 5-CNAC. The slurry washeated to 55° C. with agitation. This temperature and agitation weremaintained until the solids dissolved. Two molar equivalents (asdetermined by titration assay) of the ethanol/sodium hydroxide solutionwere added to the stirred ethanol/5-CNAC solution. The disodium 5-CNACethanol solvate began to precipitate as the sodium hydroxide solutionwas added. This addition step was exothermic and had to be controlled toprevent excessive reflux. The reactor was set up for atmosphericdistillation and about 146 L of ethanol was distilled off. The batch wascooled to less than 10° C. and held at this temperature for at about 4hours. The solid product was recovered by centrifuge filtration. Thefilter cake was placed in a drying oven and dried at 45° C. and fullvacuum for between about 16 and 24 hours. The yield of dried disodium5-CNAC monoethanol solvate was about 43.25 kg.

The XRPD spectrum for Form II is shown in FIG. 3.

Example 3 Preparation of Form III of 5-CNAC

Form III was prepared as follows. A thin layer of disodium 5-CNACmonoethanol solvate was spread in a glass tray. The tray containing thematerial was placed in a 40° C. humidity chamber set at 75% RH. Thesolids in the glass tray were periodically stirred and weighed. Thematerial was left in the humidity chamber until the sample no longerchanged weight or contained ethanol as determined by gas chromatography.This took about six days.

The XRPD spectrum for Form III is shown in FIG. 4.

Example 4 Preparation of Form IV of 5-CNAC

Form IV was prepared as follows. A one liter reactor equipped with abottom drain was charged with 375 mL of 2-butanone, 125 mL water, and125 g of disodium 5-CNAC monohydrate. The reactor contents were agitatedand heated to 50° C. The solids dissolved resulting in a biphasicsolution. The agitation was stopped and the solution allowed to separateinto two immiscible liquid layers. The bottom drain on the reactor wasused to remove and discard the lower layer. The remaining solution wascooled to ambient temperature. The product began to crystallize duringthis cooling cycle. To the resulting slurry was added 250 mL of extra2-butanone. The solid product was recovered by vacuum filtration througha sintered glass funnel. The wet cake was dried overnight in a 55° C.vacuum oven at full vacuum. The dry disodium 5-CNAC monohydrate had aweight of 54.35 g. The yield was 43%.

XRPD and DSC spectra for Form IV are shown in FIGS. 5 and 6,respectively.

Example 5 Preparation of a Mixture of Forms I and IV of 5-CNAC

A mixture of Forms I and IV of 5-CNAC was prepared as follows. A clean200 gallon glass-lined reactor was charged with 525 of acetone. Thereactor was purged with nitrogen. Agitation was started. To the stirringreactor contents were charged 35 kg of 5-CNAC. The reactor contents wereheated to between 50 and 60° C. and held at this temperature for atleast 20 minutes. During this time the majority of the solids dissolved.The reactor contents were pumped through a pressure filter into anadjacent 200 gallon glass-lined reactor. The initial reactor andpressure filter were rinsed into the second reactor with 20 L of freshacetone. An aqueous sodium hydroxide solution was prepared in a separatetank by dissolving 8.92 kg of sodium hydroxide in 44.6 L of purifiedwater. This aqueous base solution was pumped into the reactor containingthe acetone/5-CNAC filtrate. This aqueous base addition caused thereactor contents to reflux. The aqueous base tank was rinsed with 8.9 Lof fresh water into the refluxing reactor. No heat or cooling wasapplied to the reaction vessel and the reactor contents were allowed toslowly cool to ambient temperature. Cooling was applied to the reactorjacket and the reaction contents further cooled to between 0° C. and 5°C. This entire cooling cycle took between 16 and 24 hours. Theprecipitate that had formed in the reaction mixture was recovered bycentrifuge filtration. The filter cake was placed in a drying oven anddried at 60° C. and full vacuum for at least 16 hours. The yield ofdried disodium 5-CNAC monohydrate was about 39.9 kg. This 5-CNACmonohydrate was found to be a mixture of forms I and IV. The Form IV wasfound to convert to Form I over time on storage of the material.

All patents, applications, articles, publications, and test methodsmentioned above are hereby incorporated by reference.

1. Form I of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylicacid.
 2. A crystalline monohydrate of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid exhibiting an X-ray powderdiffraction pattern having at least one peak in degrees 2Θ±0.2° 2Θselected from 7.5, 10.4, 14.2, 15.0, 15.5, 16.1, 18.4, 20.8, 23.6, 24.1,24.5, 24.8, 25.4, 26.6, 27.2, 27.5, 29.6, and 31.5.
 3. The crystallinemonohydrate of claim 2, wherein the monohydrate exhibits an X-ray powderdiffraction pattern having at least two peaks in degrees 2Θ±0.2° 2θselected from 7.5, 10.4, 14.2, 15.0, 15.5, 16.1, 18.4, 20.8, 23.6, 24.1,24.5, 24.8, 25.4, 26.6, 27.2, 27.5, 29.6, and 31.5.
 4. The crystallinemonohydrate of claim 2, wherein the monohydrate exhibits an X-ray powderdiffraction pattern having at least one peak in degrees 2Θ±0.2° 2Θselected from 15.5, 24.5, and 24.8.
 5. Form II of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid.
 6. A crystalline ethanolsolvate of the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylicacid exhibiting an X-ray powder diffraction pattern having at least onepeak in degrees 2Θ±0.2° 2Θ selected from 7.5, 14.1, 16.5, 18.5, 25, and26.
 7. The crystalline ethanol solvate of claim 6, wherein thecrystalline ethanol solvate exhibits an X-ray powder diffraction patternhaving at least one peak in degrees 2Θ±0.2° 2Θ selected from 16.5, 25,and
 26. 8. Form III of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid.
 9. An octahydrate of thedisodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.
 10. Theoctahydrate of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid of claim 9, wherein theoctahyhdrate exhibits an X-ray powder diffraction pattern having atleast one peak in degrees 2Θ±0.2° 2Θ selected from 4.8, 10.4, 11.7, and14.6.
 11. (canceled)
 12. (canceled)
 13. A pharmaceutical compositioncomprising the crystalline polymorph of claim 1 and a biologicallyactive agent.
 14. The pharmaceutical composition of claim 13, whereinthe active agent is calcitonin.
 15. The pharmaceutical composition ofclaim 14, wherein the active agent is parathyroid hormone.
 16. Thepharmaceutical composition of claim 13, wherein the active agent isinsulin.
 17. The pharmaceutical composition of claim 13, wherein theactive agent is a growth hormone.
 18. A process for preparing Form I ofthe disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid ofclaim 1 comprising the steps of: (a) dissolving a monoethanol solvate ofthe disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid in amixture of acetonitrile and water; and (b) cooling the solution preparedin step (a) to an effective temperature to yield Form I of the disodiumsalt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.
 19. A process forpreparing Form I of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid of claim 1 comprising thesteps of: (a) heating an aqueous solution of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid; and (b) removing the waterfrom the solution to yield Form I of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid.
 20. A process for preparinga monoethanol solvate (Form II) of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid of claim 5 comprising thesteps of: (a) adding sodium hydroxide to a solution ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid and ethanol; and (b)precipitating Form II of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid from the solution.
 21. Aprocess for preparing the octahydrate of 5-CNAC of claim 9 maintaining(i) a monohydrate of the disodium salt ofN-(5-chlorosalicyloyl)-8-aminocaprylic acid, (ii) a monoethanol solvateof the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid, or(iii) a mixture thereof at a relative humidity of at least 75% for asufficient time to form the octahydrate.
 22. (canceled)
 23. (canceled)